Identifying risk factors for severe omicron infection in allogeneic hematopoietic stem cell transplant recipients with hematologic malignancies

Abstract Background In December 2022, a large‐scale epidemic occurred in China due to Omicron variant of SARS‐CoV‐2. This study explored risk factors for Omicron infection in transplant recipients at our institution and investigated the factors influencing the severity of SARS‐CoV‐2 Omicron infection among recipients of allo‐HSCT. Methods This single‐center study investigated totally 63 allogeneic hematopoietic stem cell transplant patients infected with Omicron variant at the Beijing GoBroad Boren Hospital Transplant Center during December 2022 and analyzed their risk factors. Results The study included 63 allogeneic hematopoietic stem cell transplant patients who developed Omicron infection. There were 34 mild and 29 moderate to severe cases. Their median age was 22 years (range, 1–65 years), with the male‐to‐female ratio being 1:1.1. Acute myeloid leukemia (53.97%), acute lymphoblastic leukemia (42.86%), and non‐Hodgkin lymphoma (3.17%) were underlying diseases. The median time between HCT and Omicron infection was 8.45 months. Significant predictive factors for moderate to severe Omicron infection included older age (p < .0001), cGVHD (p = .0195), concurrent bacterial infection (p < .0001), low absolute lymphocyte count (p = .026), low CD4/CD8 ratio (p = .0091), high CRP (p < .0001), high serum ferritin (p = .0023), high D‐dimer (p < .0001), low CD4 absolute count (p = .0057), and low B‐cell absolute count (p = .0154). A moderate to high HCT‐CI score tended to be associated with moderate to severe infection (p = .0596). Conclusion This study indicates that risk factors for severe Omicron infection include certain clinical characteristics, such as age, cGVHD, and inflammatory response.

All patients had been seen at outpatient visits or hospitalized and had symptomatic signs suggestive of COVID-19.They were all tested for SARS-CoV-2 infection.COVID-19 was diagnosed via real-time reverse transcription polymerase chain reaction (RT-PCR) or novel coronavirus antigen detection using nasopharyngeal swab or sputum samples.All suspected or confirmed SARS-CoV-2-infected HSCT recipients were placed on droplet and contact precautions, involving personal protective equipment as required by institutional regulations.

| Data collection
According to the grading criteria provided by the NIH COVID-19 Clinical Practice Guidelines, the patients were categorized as having mild, moderate, severe, and critical cases based on imaging results, SpO 2 , SpO 2 /FiO 2 , hypotension, acute respiratory distress syndrome (ARDS), presence of respiratory failure, septic shock, and/or multiorgan dysfunction.Adverse outcomes were set as progressive respiratory failure (i.e., persistent worsening of SpO 2 ), continuous progression of ARDS, admission to intensive care unit (ICU), and/or death.Factors influencing critical illness due to SARS-CoV-2 infection were assessed based on available laboratory parameters (C-reactive protein, white blood cell count, lymphocyte count, neutrophil count, lymphocyte subpopulation ratios, cytokine levels, and soluble CD25 levels).The standardized HCT comorbidity index (HCT-CI) was adopted for reporting comorbidities. 10sease duration was set as the time from SARS-CoV-2 infection diagnosis to the recorded resolution of infection or death.Infection status was considered persistent when no clinically significant improvement signs existed or resolved if all signs and symptoms were resolved and the patient had completed the planned course of infection treatment.

| Statistical analysis
Descriptive statistical methods were used to compare baseline demographic characteristics.Data analysis of binary variables was conducted with chi-square and Fisher-exact tests.Multinomial variables were explored with Cochran-Armitage trend tests and Fisher-exact tests.Using t tests and rank sum tests, continuous variables were studied.SAS 9.4 software was adopted for the statistical analyses.

| Treatment after SARS-CoV-2 infection
Symptomatic treatment with medications was administered to patients with symptoms restricted to the upper respiratory tract, the normal blood oxygen saturation, and no radiological features of pneumonia, according to COVID-19 Clinical Practice Guidelines provided by the NIH. 11Corticosteroids, tocilizumab, and/or JAK2 inhibitors were added in cases of progressive respiratory failure and increased inflammatory parameters.If bacterial or fungal coinfection was suspected, empirical antibiotic treatment was given.

Management of immunosuppression was determined in consulta-
tion with hematopoietic stem cell transplant physicians and pulmonology physicians but usually involved gradual discontinuation or reduction of maintenance therapy.Calcineurin inhibitors were temporarily discontinued or reduced when Paxlovid (nirmatrelvir/ritonavir) was initiated, followed by close therapeutic drug monitoring (TDM) thereafter, paying attention to Paxlovid (nirmatrelvir/ritonavir) drug interactions.Patients with COVID-19 were given 0.5-1 mg/kg methylprednisolone for anti-inflammatory treatment, depending on the severity of their lung lesions.Some patients with severe pneumonia manifestations, including hypoxemia, received increased doses of corticosteroids.
This cohort of patients was in complete remission when they were infected with COVID-19, and all of their bone marrow status was complete donor type.We also did not observe an effect of COVID-19 infection on the chimerism rate.

| Severity of omicron infection
Fifty-four percent of the infected individuals had mild symptoms, while 46% showed moderate to severe symptoms.Clinical   13,14 The overall mortality of patients in our cohort, where only a minority had been vaccinated, was 4.76%.This might be due to the use of antiviral drugs or infection caused by different SARS-CoV-2 strains.However, further studies are warranted due to the different vaccine backgrounds of the patients in this cohort study, further studies may be needed. 15,16portant risk prediction factors for severity of COVID-19 included different levels of immune cells, inflammatory factors, D-dimer levels, cGVHD, and bacterial infection.In HCT recipients, factors significantly increasing the mortality rate compared with the general population were multifaceted, mainly due to severe immune dysregulation, long-term immune suppression, GVHD, and reduced blood cells. 17delay antibody production, and worsen the disease. 19Previous studies in China also found that a reduction in B-cell levels is closely related to delayed clearance of the virus, possibly due to the increased proportion of plasmablasts in peripheral blood, influencing humoral immune function and reducing the generation rate of specific antibodies. 20In follow-up research, it was shown that the reduction in CD4+ T/CD8+ T ratio was relatively stable in both healthy individuals and recovering patients and did not change gradually with recovery from the disease. 21Therefore, this indicator can more specifically identify high-risk groups that may experience progression to severe illness, especially in people over 50 years old.In addition, some studies also suggest that the CD4+ T/CD8+ T ratio can be a vital identification indicator for severe COVID-19 and the need for ICU support treatment. 22,23evious studies indicated that there was no obvious relationship between HCT-CI and survival.However, in our retrospective study, HCT-CI scores for patients with medium to high risk were associated with a trend toward moderate to severe infection.This finding is inconsistent with the conclusions drawn by Sharma and Mushtaq et al. 13,24 ; it may be caused by a relatively smaller sample size in previous studies or differences in viral infection subtypes; therefore, further extensive statistical analysis studies are needed for validation.
As reported in previous studies, our center's statistical results indicate that high serum ferritin levels showed a relationship to COVID-19 severity and mortality. 5,14However, there is still controversy on the correlation between elevated CRP level and poor prognosis.Mushtaq's study found no clear correlation between high CRP levels and poor prognosis, 24 while others believe that high CRP levels usually indicate poor prognosis. 25Our center's research suggests that high C-reactive protein predicts poor prognosis for COVID-19 patients, which may be associated with the use of baseline immunosuppressive drugs in our center, causing the index to remain within a relatively normal range at the onset of the disease.Abnormalities in inflammatory factors appear only when the disease worsens, and the inflammatory state at the onset of the disease is already at a high level, indicating severe illness and poor prognosis.
In a previous single-center study on pediatric HSCT recipients, Averbuch et al. found that HSCT recipients with chronic GVHD, especially those concurrently using immunosuppressive drugs including mycophenolate mofetil (MMF), were more probably to develop severe or critical illness after SARS-CoV-2 infection. 26This may be resulted from the concurrent use of immunosuppressive drugs, a higher proportion of medium-risk immune deficiency scores, and a higher likelihood of coinfection with other pathogens.In a multicenter study led by Sharma, the use of immunosuppressive drugs within 6 months before SARS-CoV-2 infection exerted no clear effect on the prognosis of COVID-19. 13However, further subgroup analyses were not possible due to the small sample size.Some studies from other countries suggest that poor prognosis in such patients is related to factors including low immune response and low antibody titers after vaccination. 27Nevertheless, in our center's study, most patients did not receive a full course of vaccination, and there were some differences compared with other studies.The efficiency of the immune response requires further analysis.
In addition to above-mentioned risk factor analysis, statistical analysis was performed on the vaccination status of patients at our center.
Among the 63 HSCT recipients infected with SARS-CoV-2, only seven had received the SARS-CoV-2 inactivated vaccine, with four receiving two doses of the vaccine and three receiving just one dose.The last vaccination was more than 1 year before the infection.During the 3-year COVID-19 pandemic, the protective effect of vaccines for susceptible populations has been widely recognized in reducing infections and mortality rates. 28Studies have shown that vaccinated HSCT recipients have relatively better prognosis but that those who have not been vaccinated at the time of infection usually have more severe disease.In this immunocompromised population, encouraging vaccination can benefit HSCT recipients when they become infected with SARS-CoV-2. 29However, with the emergence of variant strains, the protective efficiency of existing vaccines has declined to varying degrees, and some studies even suggest that the antibody titer against the original strain increases significantly in people who have obtained three doses of inactivated vaccine but that the specificity of the antibody titer against Omicron decreases. 30Typically, the effectiveness of SARS-CoV-2 infection, hospitalization, and mortality rates declines over time, with Omicron variant baseline vaccine effectiveness levels being significantly lower than those for other variants.In cancer patients, particularly those with hematological malignancies, breakthrough infections are more probably to occur than in the general population, and this group of patients usually has a higher probability of developing severe and critical illness. 31Therefore, other preventive measures (including wearing masks and maintaining physical distance) may be necessary for long-term pandemic management. 32

| CONCLUSION
To conclude, this study has found that omicron infection in allo-HSCT setting has caused more pneumonia and more reactivation in advanced infection pattern (including moderate, severe, and critical).
In addition, the risk factors of the severity of omicron infection in patients after allo-HSCT include age, cGVHD, and inflammatory reac-
T A B L E 3 Fisher-exact or chi-square analysis of factors associated with disease severity in HCT recipients diagnosed with COVID-19.